The release of neurotransmitters from presynaptic nerve terminals by the fusion of transmitter-filled secretory vesicles with the nerve terminal membrane is critical for the transfer of information throughout the nervous system. This release is gated by the influx of calcium ions via voltage-gated ion channels and the control of channel availability is a major mechanism in the control of synaptic strength, and hence, synaptic pathways. We are exploring the function of these calcium channels by several different approaches. We are examining the role of Ca channels in the presynaptic nerve terminal using the giant presynaptic terminal of the chick ciliary ganglion as an experimental model. Our main recent findings have include the examination of the mechanism whereby calcium ions are extruded from the nerve terminal. For this we stained the nerve terminals for calcium pumps and the sodium-calcium exchangers and compared their localization with the transmitter release sites. Contrary to expectations, the exchangers were at locations distant from the transmitter release sites whereas the pumps were located at the release sites themselves. Second, we have demonstrated that activation of presynaptic Ca channels results in a depletion of Ca ions in the synaptic cleft. Third, we have examined the class and location of G proteins that are involved in the fast modulation of transmitter release via the presynaptic calcium channel. We determined that the pertussis-toxin sensitive G proteins of the Go/i family are the primary, and possibly only, modulator of pathways activated by neurotransmitters but we also demonstrated that other G protein families can also modulate these channels, though the mechanism of activation of these remains to be determined. Finally, we have unambiguously demonstrated that cysteine string proteins, integral componenents of the secretory vesicle, can up-regulate presynaptic Ca channels, a finding that implies this protein in the priming of the transmitter release site.